Increased Neurite Orientation-Dispersion and Density in the TgCRND8 Mouse Model of Amyloidosis: Inverse Relation with Functional Connectome Clustering and Modulation by Interleukin-6

Luis M. Colon-Perez; Kristen R. Ibanez; Mallory Suarez; Kristin Torroella; Kelly Acuna; Edward Ofori; Yona Levites; David E. Vaillancourt; Todd E. Golde; Paramita Chakrabarty; Marcelo Febo

Excess production and oligomerization of the β-amyloid (Aβ) protein, the main constituent of amyloid plaques, substantially modifies neuronal morphology (Biscaro et al., 2009; Spires and Hyman, 2004) . Important, Aβ alters neuronal homeostasis and synaptic plasticity by modifying the extracellular environment of neuronal soma, axons, and synapses (Mueggler et al., 2004; Sykova et al., 2005) . Aβ is implicated in the formation of dystrophic 'neurites' (Sadleir et al., 2016; Zhang et al., 2009) , deficits in synaptic plasticity and excitability (Cummings et al., 2015; Varga et al., 2015) , cell membrane protein aggregation (Shrivastava et al., 2017) , reduced integrity of major fiber tracts (Mayo et al., 2017; O'Dwyer et al., 2011; Teipel et al., 2014) and impaired activity in resting state networks (Hedden et al., 2009; Jones et al., 2016) . In addition, Aβ is immunogenic (Dalgediene et al., 2013) , leading to the increased activated microglia in the brain (Mirzaei et al., 2016; Serriere et al., 2015) . Positron emission tomography (PET) studies using microglia-or Aβspecific radiotracers provide compelling evidence of an overlapping presence of activated microglia and amyloid burden in Alzheimer's disease (Kreisl et al., 2013; Liu et al., 2015; Mirzaei et al., 2016; Parbo et al., 2017; Schuitemaker et al., 2013) . For instance, a longitudinal study identified a transient elevation in microglia early in mild cognitive impairment (MCI) which peaked later in Alzheimer's disease (Fan et al., 2017) . Aged transgenic mice expressing familial Alzheimer's mutations to amyloid precursor protein and presenilin-1 with deletion of exon-9 (APP/PS1dE9) had higher in vivo cortical and hippocampal accumulation of an activated microglial-targeted radiotracer, 18kD translocator protein (TSPO), than aged wildtype or young Tg mice (Liu et al., 2015) . Taken together, the above findings strongly suggest that accrual of Aβ plaques and concomitant reactive microgliosis may underlie pathologic dysfunction in Alzheimer's by causing deleterious changes to brain parenchymal microstructure. In this study, we asked the question whether we can utilize high field diffusion magnetic resonance imaging (dMRI) to quantitatively assess amyloid pathology and immune-related mechanisms in a mouse model of Alzheimer's disease and establish their mechanistic links with intrinsic brain activity measured by resting state functional MRI (fMRI) (Brown et al., 2018) .